Novel Prophylactic HIV Vaccines Based on rAAV Vectors

描述（由申请人提供）：本HIVRAD项目的总体目标是开发基于重组腺相关病毒（rAAV）载体的第二代HIV -1疫苗。本申请中提出的研究建立在我们正在准备进行人体试验的第一代rAAV /HIV疫苗的经验基础上。虽然第一代疫苗是一个有希望的候选疫苗，但我们认为仍有很大的改进空间。基于我们的初步数据，我们在项目1 -4中开发了一系列假设驱动的实验来实现这一目标。会议将拟定两个主要主题。首先，我们将通过(i)显著增加疫苗基因传递（项目1和2）和（ii）直接参与和修饰宿主免疫反应（项目1和3）来增强抗原特异性T细胞对疫苗的反应。其次，通过一种新颖和创新的方法，我们将利用rAAV载体将预定特异性的人抗体基因转移到骨骼肌中，从而产生血清抗体来中和HIV -1原代分离物（项目4）。这些主题的结合将构成第二代rAAV /HIV疫苗的基础。该规划的两个重要和预期的副产品将是：(i)更好地了解基于基因的疫苗的实际工作原理（项目3）；(b)改良的一般基因传递到肌肉的载体（项目2）。整个程序将由四个核心支持。核心A是行政办公室，因此将协调该计划并确保拟议研究的及时执行。核心B将作为非人类灵长类动物的中心测试设施。核心C是非人灵长类动物免疫学核心，直接隶属于核心b。核心D支持该计划的病毒载体生产。

DESCRIPTION (provided by applicant): The overall goal of this HIVRAD Program is to develop a second generation HIV -1 vaccine based on recombinant adeno-associated virus (rAAV) vectors. The proposed research in this application builds on our experience with a first generation rAAV /HIV vaccine that is being readied for human trials. Although the first generation vaccine is a promising candidate, we believe that substantial room for improvement remains. Based on our preliminary data, we have developed a series of hypothesis driven experiments in Projects 1 -4 to achieve this goal. Two major themes will be developed. First, we will enhance antigen- specific T cell responses to the vaccine by (i) significantly augmenting vaccine gene delivery (Projects 1 and 2) and (ii) directly engaging and modifying host immune responses (Projects 1 and 3). Second, through a novel and innovative approach, we will generate serum antibodies that neutralize primary isolates of HIV -1 by using rAAV vectors to transfer human antibody genes of predetermined specificity to skeletal muscle (project 4). The convergence of these themes will form the basis of the second-generation rAAV /HIV vaccine. Two important and intended by-products of this Program will be: (i) a better understanding of how gene-based vaccines actually work (Project 3); and, (b) improved vectors for general gene delivery to muscle (Project 2). The entire Program will be supported by four Cores. Core A is the Administrative Office, and as such will coordinate the Program and ensure the timely execution of the proposed research. Core B will serve as the central testing facility for non-human primates. Core C is the non-human primate immunology core and is directly affiliated with Core B. Core D supports viral vector production for the Program.